Post on 21-Jan-2022
The role of fixed-dose combination therapy in
the management of hypertension
Prof. Davor Miličić
Department of Cardiovascular Diseases
University of Zagreb
Croatia
Global burden of hypertension
Hypertension is the primary major cause of premature death
972 million with hypertension estimated in 2000 predicted to rise to 1.56 billion by
2025
80% increase in hypertension expected in economically developing regions
Kearney et al. Lancet 2005;365:217-23
WHO findings on hypertension
The #1 global risk factor for premature mortality causing 7.5 million deaths per
annum
Responsible for 51% of stroke and 45% of ischaemic heart disease deaths
Global health risks. WHO 2009
Management of hypertension today
The most common CV disorder affecting 27-55% of adults1
A major risk factor for CV and renal disease1,2
Level of protection achieved against CV diseases is related to the degree of BP
reduction2
However, only 20-55% of treated patients achieve and maintain internationally
recognised targets 1,2
1. Wolf-Maier K et al. Hypertension 2004;43:10-17.
2. Struijker-Boudier H et al. Int J Clin Pract 2007;61:1592-602.
Poor BP control in practice populations1
1. Paulsen M et al. Family Practice 2011; published online, May 19, 2011
2. Burnier M et al. Int J Clin Pract 2009;63:790-8.
Cross-sectional survey of 5413 hypertensive patients in Denmark1
“Approximately 7 out of 10 hypertensive patients in
Europe do not achieve target BP” 2
Most treated patients in Eastern Europe do not achieve target BP
Adapted from Grassi G et al. Eur Heart J 2011;32:218-25.
Uncontrolled BP
% of patients displaying office
BP controlled (<140/90 mmHg)
or uncontrolled ≥140/90 mmHg)
7,860 treated patients in the BP-CARE survey in Central
and Eastern Europe (9 countries)
Causes of inadequate BP control
Patient/society Misdiagnosis Doctor
Poverty, lack of health
insurance
Improper BP recording
technique
Physician inertia, poor
motivation to deliver patient
education
Lack of education, health
beliefs
White coat syndrome Multiple guidelines
Difficulty in implementing
lifestyle change
Masked hypertension Insufficient use of multiple
agents or insufficient dosing
Compliance issues relating
to cost, side-effects,
inconvenience, pill burden
Failure to identify secondary
hypertension
Authentic resistant
hypertension
Interactions with other
prescribed medication
Adapted from Elijovich F et al. Ther Adv Cardiovasc Dis 2009;3:231-40.
Inadequate BP control is associated with increased risk of fatal events
n=5128Fully adjusted models§
Hazard ratio (95% CI)
Hypertension category All-cause mortality CVD mortality
Treated controlled 1.00 1.00
Treated uncontrolled 1.57 (1.28-1.91)* 1.74 (1.36-2.22)*
Untreated 1.34 (1.12-1.62)* 1.37 (1.04-1.81)**
Risk of CVD mortality increased by 74% in uncontrolled hypertensives 1
Data from NHANES III in US hypertensive adults (1988-2006)§ adjusted for age, race/ethnicity, smoking, hypercholesterolaemia, obesity, diabetes, CKD, HF, stroke
* p<0.01; ** p<0.05
1. Gu Q et al. Am J Hypertens 2010;23:38-45.
Multiple therapies are required to achieve target BP1
Number of drugs needed to achieve BP 140/90 mmHg
Patients 1 2 3 4 5 +
Men (all ages) n 333 400 408 248 104
Men (all ages) % 22.3% 26.8% 27.3% 16.6% 7.0%
Women (all ages) n 154 263 387 317 219
Women (all ages) % 11.5% 19.6% 28.9% 23.7% 16.3%
1. Adapted from Marshall T. J Hum Hypertens 2005;19:317-9.
2. Gradman A et al. J Am Soc Hypertens 2010;4:42-50.
3. Mancia et al. J Hypertens 2009; 27:2121-58
≥75% of patients require multiple therapies to achieve target 2
Evidence has continued to grow that in the vast majority of hypertensive patients, effective
BP control can only be achieved by combination of at least two antihypertensive drugs 3
Pathophysiology of essential hypertension: multiple causes
Adapted from Sever P, Messerli FH. Eur Heart J 2011;32:2499-506.
• Autoregulation
• Ion transport inhibitors
• Sympathetic nervous system
• Renin-angiotensin-aldosterone system
• Other hormonal systems
• Renal mechanisms
• Vascular wall contractility and structure
• Rarefaction
Rationale for combination therapy:1
Combines drugs acting in different physiological systems1
Blocks counter-regulatory responses1
Treats moderate/severe hypertension1
Reduces BP variability vs monotherapy1,3
>75% of patients require combination therapy
to achieve BP target2
1. Sever P, Messerli FH. Eur Heart J 2011;32:2499-506.
2. Gradman A et al. J Am Soc Hypertens 2010;4:42-50.
3. Rothwell P et al. Lancet 2010;375:895-905.
Criteria for an optimal fixed dose combination1
Component drugs should act via different and complementary mechanisms
BP-decreasing effect of combination is greater than that of components alone
Incidence of side-effects should be reduced or at least not increased
Combination should be efficacious in once-daily treatment
Combination should provide protection against target organ damage
Combination therapy is recommended in ESH/ESC guidelines2
1. Struijker-Boudier H et al. Int J Clin Pract 2007;61:1592-602.
2. Mancia G et al. J Hypertens 2009;27:2121-58. DOI:10.1097/HJH.0b013e328333146d.
Combination therapy is more effective than increasing the dose of monotherapy
Adapted from Wald D et al. Am J Med 2009;122:290-300.
A meta-analysis of 42 trials and 10968 patients shows that combining two different antihypertensive
classes gives approximately 5 times greater additional fall in BP than doubling the dose of a single drug.
Combination of complementary therapies may improve drug efficacy
Adapted from Law M et al. BMJ 2003;326:1427-31.
Effects of 2 different drugs on BP separately and in combination
(summary results from 119 randomised placebo-controlled comparisons from 50 trials)
Fixed dose combinations improve compliance and persistence
*Patients regarded as persistent if remaining on therapy during the last month
** Compliance measured by Medication Possession Ratio (MPR)
Adapted from Hess G. Pharmacy & Therapeutics 2008;33:652-66.
Retrospective cohort of 14449 hypertensive patients receiving fixed dose combination and switched
to free combination
Guidelines recommend use of combination therapy
JNC 7
2003 1“More than two-thirds of hypertensive individuals cannot be controlled
on one drug and will require two or more antihypertensive agents
selected from different drug classes.”
ESH/ESC
2007 2“Regardless of the drug employed, monotherapy allows to achieve
BP target in only a limited number of hypertensive patients. Use of
more than one agent is necessary to achieve target BP in the
majority of patients.”
ESH 2009 3 “Evidence has continued to grow that in the vast majority of hypertensive
patients, effective BP control can only be achieved by combination of at
least two antihypertensive drugs.”
1. Chobanian A et al. JNC 7 guidelines. Hypertension 2003;42:1206-52.
2. Mancia G et al. ESH/ESC guidelines. J Hypertens 2007;25:1751-62.
3. Mancia G et al. Reappraisal of European guidelines. Blood Press 2009;18:308-347.
Complementary modes of action
+
Amlodipine3
Potent calcium channel blocker
↑ Vasodilatation
↓ Peripheral resistance
↓
↓ Blood pressure
Bisoprolol1,2
Highly selective beta blocker
Sympathetic control
Blocks sympathetic effects
↓
↓ Heart rate
↓ Cardiac output
↓ Blood pressure
Bisoprolol and amlodipine short product characteristics
1. Cruickshank JM. Int J Cardiol 2007;120:10-27;
2. Palatini P et al. Drugs 2006;66:133-144.
3. Murdoch D and Heel RC. Drugs 1991;41:478-505.
Complementary cardioprotection beyond blood pressure control
1. Murdoch D and Heel RC. Drugs 1991;41:478-505;
2. Cruickshank JM. Int J Cardiol 2007;120:10-27;
3. Palatini P et al. Drugs 2006;66:133-144.
Concor AM provides a significant relative reduction in blood pressure within 4 weeks
Adapted from Rana R & Patil A. Indian Pract 2008;61:225-34.
Observational open-labelled, non-comparative survey of 801 patients with stage 2 hypertension in
169 indian centres.
82.5% of patients achieved BP goal (<140/90 mmHg)
Concor AM significantly reduces heart rate
Adapted from Rana R & Patil A. Indian Pract 2008;61:225-34.
Observational open-labelled, non-comparative survey of 801 patients with stage 2
hypertension in 169 Indian centres.
Good tolerability profile: adverse events
After 4 weeks of treatment with Concor AM (5 mg + 5 mg) once daily,
90% of patients report good to excellent tolerability
Adapted from Rana R & Patil A. Indian Pract 2008;61:225-34.
Observational open-labelled, non-comparative survey of 801 patients with stage 2
hypertension in 169 Indian centres.
Adverse events reported during the study
Conclusion
Hypertension is the number one global risk factor for premature
mortality
Approximately 7 out of 10 hypertensive patients do not achieve target
BP
Causes for inadequate BP control involve many factors, one of the
most important being poor patient compliance
More than 75% of patients require combination therapy to achieve
target BP
Fixed dose combinations significantly improve patient compliance and
number of controlled hypertensive patients